Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C

摘要: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, molecular mechanisms causing neurodegeneration in this are unknown. Here we report altered expression and/or mislocalization TAR-DNA binding protein 43 (TDP-43) both NPC mouse human neuronal model disease. We also neuropathologic study patient’s brain, showing that while TDP-43 below immunohistochemical detection nuclei cerebellar Purkinje cells, it has predominant localization cytoplasm these cells. From functional point view, mislocalization, occurs experimental system, associated with specific alterations controlled genes. Most interestingly, treatment N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore nuclear localization. Taken together, results studies extend role beyond Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer (AD) spectrum. These findings may open novel research/therapeutic avenues for better understanding proteinopathy mechanism.